Abstract
Hydrogen sulfide (H2S) is a gaseous neuromodulator endogenously produced in the brain by the enzyme cystathionine β-synthase (CBS). We tested the hypothesis that H2S acts within the anteroventral preoptic region of the hypothalamus (AVPO) modulating the production of prostaglandin (PG) E2 (the proximal mediator of fever) and cyclic AMP (cAMP). To this end, we recorded deep body temperature (Tb) of rats before and after pharmacological modulation of the CBS–H2S system combined or not with lipopolysaccharide (LPS) exposure, and measured the levels of H2S, cAMP, and PGE2 in the AVPO during systemic inflammation. Intracerebroventricular (icv) microinjection of aminooxyacetate (AOA, a CBS inhibitor; 100pmol) did not affect basal PGE2 production and Tb, but enhanced LPS-induced PGE2 production and fever, indicating that endogenous H2S plays an antipyretic role. In agreement, icv microinjection of a H2S donor (Na2S; 260nmol) reduced the LPS-induced PGE2 production and fever. Interestingly, we observed that the AVPO levels of H2S were decreased following the immunoinflammatory challenge. Furthermore, fever was associated with decreased levels of AVPO cAMP and increased levels of AVPO PGE2. The LPS-induced decreased levels of cAMP were reduced to a lesser extent by the H2S donor. The LPS-induced PGE2 production was potentiated by AOA (the CBS inhibitor) and inhibited by the H2S donor. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated during endotoxemia favoring PGE2 synthesis and lowering cAMP levels in the preoptic hypothalamus.
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